The clinical symptoms produced in the course of allergic reaction are the result of an early specific immune response and a late inflammatory reaction. The inhaled allergens (e.g. pollens, mite dust) mediate the early phase by stimulating high affinity immunoglobulin (I.sub.g E) receptors e.g. mast cells and basophils which in turn release histamine and cytokines. This early phase lasts for about 30 minutes. The cytokines released from mast cells and basophils then mediate the late phase by recruiting inflammatory cells into the nasal and upper respiratory tract passages (Serafin, WE, In Goodman and Gillmans "The Pharmacological Basis of Therapeutics", Hardmen, Ja; Limbird, L,E eds, Mc Graw-Hill, N.Y., 1996, 659-682). The influx of eosinophils, macrophages, lymphocytes, neutrophils and platelets starts the vicious inflammatory cycle. This late phase lasting for 8-48 hours amplifies the initial immune response which in turn triggers the release of more inflammatory cells (Townley RG and Okada, C, Annals of Allergy, 68, 1991, 190-196).
Seasonal allergic rhinitis (hay fever) is caused by deposition of allergens on the nasal mucosa resulting in an immediate hypersensitivity reaction. If the allergens (e.g. dust mite) are carried to the lower airways (i.e. bronchioles), in susceptible subjects, the result is bronchoconstriction of the airways (i.e. asthma). The allergen-induced release of leukotrienes, the 5-lipoxygenase products of arachidonic acid metabolism in activated airway cells, is critical in the pathophysiology of asthma. Leukotrienes are produced by mast cells, eosinophils, neutrophils and alveolar macrophages. The use of specific leukotriene receptor antagonists or 5-lipoxygenase pathway inhibitors results in increased airflow and reduction of symptoms in asthmatic patients (Henderson W R, Jr., Annals of Allergy, 72, 1994, 272-277). Immunologic concepts of asthma and related allergic disorders are undergoing revolutionary changes. All asthma are now proposed to have an allergic basis and all chronic allergic disorders have a basal ongoing inflammation which is never fully resolved. In the annual meeting of the European Academy of Allergy and Clinical Immunology which took place in Greece, Jun. 1-5, 1997, the clinical implications of minimal persistent inflammation (MPI) have been emphasized. A mild presence of inflammatory cells and ICAM--1 receptors on epithelial cells has been demonstrated even during asymptomatic periods in allergic subjects. So the correct treatment of allergic disorders should address allergic inflammation and not just the symptoms. In this annual meeting a redefinition of allergic disorders was also emphasized. Rhinitis and asthma were pooled together as the inflammatory mechanisms represent a common unifying concept for the pathogenesis of allergic disorders. Allergic rhinitis and bronchial asthma frequently co-exist. Upto 40% of rhinitics have concomitant asthma and up to 80% of asthmatics also have rhinitis. Rhinitics have upto three fold greater risk of developing asthma as the inflammatory mediators, constantly being released in the airways, may produce alterations in the airway epithelium such that an allergic person becomes prone to asthmatic attacks (Wenzel, S. E, Annals of Allergy, 72, 1994, 261-271). It was thus proposed that treating nasal and airway inflammation may be a key to asthma control. It was concluded that development of therapeutic strategies for the prevention and prophylaxis of respiratory allergy should be approached rather than the treatment except for asthmatic emergencies.
Thus it is self-evident that although antihistamines (second generation H.sub.1 -blockers) are the most widely used agents for the treatment of allergic conditions (Gong, H, Tashkin, D. P, Dauphinee, B et al., J.Allergy. Clin. Immunol., 85, 1990, 632-641), NSAIDS can also prove to be very useful as anti-inflammatory drugs. To date, NSAIDS like aspirin, its analogues and even unrelated chemical moieties could not be used in allergic disorders because of the precipitation of a pseudoallergic reaction in aspirin intolerant patients. Despite their anti-inflammatory effects, almost all NSAIDS potentiate I.sub.g E-mediated histamine release from mast cells and basophils resulting in vasomotor rhinitis, urticaria and bronchial asthma in these patients (Bianco, S, Robuschi, M, Petrigni, G et al., Drugs, 46, 1993, 115-120).
However, one unique NSAID stands out from the rest. Nimesulide, a sulfonanilide NSAID, is well tolerated by patients with all allergic disorders and aspirin idiosyncrasy (Casolaro, V, Meliota, S, Marino, O et al., J. Pharmacol. Exp. Ther., 267, 1993, 1375-1385). It has a profound antihistaminic, antianaphylactic activity (Berti, F, Rossoni, G, Buschi, A et al., Arznemittel Forschung, 40, 1990, 1011-1016). in addition to its potent anti inflammatory action (Serafin, W E, 1996; Bellusi, L, Passali, D, Drugs (46) Suppl. 1, 1993, 107-110). Nimesulide inhibits the allergen induced immunologic release of histamine and also improves bronchial responsiveness in asthmatic patients exposed to bronchoconstrictors (Casolaro, V, et al. 1993; Berti, F, et al. 1990).
All above studies only indicated the possible extension of antiinflammatory action of Nimesulide for control of inflammation of upper respiratory tract. However, the use of Nimesulide as an antiasthmatic due to antiallergic and leukotriene inhibiting activities of Nimesulide has not been reported so far, and by careful experimentation and application of scientific logic the inventors combined Nimesulide with Cetirizine in different proportions and carried out several experiments to see the utility of such a combination for use as an antiasthmatic agent. It has been surprisingly observed by the inventors and described in the present invention that a combination of Nimesulide with Cetirizine is a synergistic composition and of immense utility in asthma.
Other anti-inflammatory drugs used in chronic rhinitis, chronic bronchitis and bronchial asthma are cromolyn sodium, nedocromil and glucocorticoids. The glucocorticoid therapy is not without an accompanied risk of myriad side effects (Serafin, W E, 1996). Cromolyn sodium and nedocromil can only be given by inhalation, only about 1% of an oral dose of cromolyn is absorbed. Even when inhaled, cromolyn sodium has to be taken 4 times daily due to its short half-life of 45-100 minutes. Nedocromil is reported to leave a bad taste in mouth. Several other anti-inflammatory agents have been assessed, mainly as steroid-sparing agents. These include methotrexate, gold, troleandomycin, hydroxychloroquine, dapsone and cyclosporin. But their efficacy has not been firmly established (Szefler, S., Antiinflammatory drugs in the treatment of allergic diseases., Medical Clinics of North America, 76, 1992, 953-975).
U.S. Pat. No. 5,658,948 granted to ALLERGAN INC., discloses a formulation and method including an acceptable drug, such as Prostaglandins, Flurbiprofen, Keterolac Tromethamine, Cetirizine HCI, Indomethacin and Bufrolin, which are interactive with benzalkonium chloride to form a precipitate along with benzalkonium chloride acting as a preservative and an amino acid having enough positive charge at the pH of the formulation and/or Tromethamine present in an amount sufficient to interface with the interaction between the drug and benzalkonium chloride in order to maintain the preservative activity of the benzalkonium chloride. Further, the use of Lysine, L-arginine, or Histidine is also useful in reducing the cytotoxicity of the formulation.
U.S. Pat. No. 5,627,183 granted to SEPRACOR INC., discloses methods for utilizing optically pure (+) Cetirizine for the treatment of urticaria in humans while avoiding the concomitant liability of adverse effects associated with the racemic mixture of Cetirizine.
U.S. Pat. No. 5,419,898 granted to SENJU PHARMACEUTICAL Co., LTD., discloses an anti-allergic composition for opthalmic or nasal use, comprising cetirizine or a salt thereof as an active ingredient. The antiallergic composition may further contain a cyclodextrin compound, as well as surfactant and/or a water soluble polymer.
WO 9406429 granted to SEPRACOR INC., discloses methods and compositions utilizing optically pure (-) cetirizine for the treatment of seasonal and perennial allergic rhinitis in humans while avoiding the concomitant liability of adverse effects associated with the racemic mixture of cetirizine. The optically pure (-) isomer is also useful for the treatment of allergic asthma and chronic and physical urticaria. (-) Cetirizine is an inhibitor of eosinophil chemotaxis and is therefore useful in the treatment of other conditions related to eosinophilia such as allergic asthma, seasonal allergic rhinitis, atopic dermatitis, some parasitic diseases, some chronic obstructive lung diseases and certain gastrointestinal and genitourinary disorders.
No pharmacological composition has been reported in literature as well as no product is available where Nimesulide and salts thereof is employed in combination with second generation antihistamine. Fixed dose drug combinations are rapidly being re-introduced in clinical practice after several years of ostracism as these have the potential of acting synergistically and predictably.
It is the objective of the present invention to provide a novel antileukotriene, antihistaminic, anti-allergic and antiinflammatory composition containing Nimesulide and salts thereof and Cetirizine.
It is the further objective of the present invention to provide a novel process for the manufacture of an antileukotriene, antihistaminic, anti-allergic and antiinflammatory composition containing Nimesulide and salts thereof and Cetirizine.
It is a further objective of the invention to provide a novel metered dose inhaler nasal delivery system for the above composition.
It is a further objective of the invention to provide a novel injectable delivery system of the above composition.
It is a further objective of the invention to provide a novel topical delivery system for the above composition.
It is a further objective of the invention to provide the above composition to be taken orally by way of a pedriatic suspension/capsule/tablet.